Israel Prize winner Prof. Moshe Oren: "We won't allow the tumor to escape the therapy"
Cocktails. That's the key word in the future fight against cancer, says Prof. Moshe Oren of the Weizmann Institute's Molecular Cell Biology Department, a pioneer of research into the molecular mechanisms of cancer. Advanced medicine will be customized on the basis of a patient's individual genetic profile. If a malignant disease is diagnosed, physicians should be able to prescribe effective treatments with a high likelihood of a cure. Oren, winner of the 2008 Israel Prize, believes these future cancer treatments will consist of a blend of several drugs, similar to the antiviral cocktails that currently keep AIDS at bay. "No single cancer therapy will probably work sufficiently well, and even if it does, the tumor might develop resistance to the drug," he says. "But if the patient receives drugs targeting two different mechanisms, the tumor is much less likely to 'escape' this onslaught."
The major advantage of personalized, molecular drugs is fewer and weaker side effects: These therapies will kill the tumor without killing the patient. But how will the drugs be tailored to each patient's needs? Says Oren: "The drug cocktail will target the dominant genetic defects in each person's cancer. Hopefully, we won't have to invent the cocktail each time from scratch but will identify groups of people that respond to certain drug combinations, based on their particular genetic makeup. The right patients should get the right drugs at the right time, as people with cancer often don't get a second chance."
A number of molecular therapies currently tested in clinical trials are based on Oren's research into p53, the tumor suppressor gene that is most frequently altered in human cancers. The p53 gene is known as the "guardian of the genome" because it puts the brakes on cancer when the cell's genome is damaged. When these "brakes" are not functioning properly, the road to cancer remains open. In 1983, together with collaborators, Oren was the first to isolate and clone p53, and in subsequent years, he made major discoveries about the way p53 works in normal and cancerous cells. Here he discusses the latest developments in p53 research, including his own most recent findings.
Therapies based on p53
"We now know that in the vast majority of cancerous tumors the tumor suppressor function of p53 is at least partially defective; but the nature of the defect varies greatly from one tumor to another. In about half of all cancers, the p53 gene itself is directly impaired. In such cases, the most appealing treatment strategy, now tested in clinical trials in China, is to deliver working p53 copies to cells by gene therapy. In other cases, the defect lies either in the genes controlling p53 or in the molecular machinery p53 uses to exert its effects – 'upstream' or 'downstream,' as the scientists say, from p53. In these instances, the therapy is aimed at correcting the defect in order to allow p53 to perform its cancer-blocking function.
"About ten years ago, we discovered one crucial 'upstream' mechanism: a genetic switch called Mdm2 that controls p53 activity. Mdm2's job is to make sure p53 is present in the cell in just the right amount by continuously destroying surplus p53 protein. If Mdm2 becomes overly active, it might destroy too much p53, depriving the cell of a vital tumor suppressor mechanism. Such excessive activity of Mdm2 is found in 10% to 20% of all cancers, particularly in sarcomas and in certain types of leukemia. Drugs that block Mdm2 so as to prevent an overzealous destruction of p53 are currently in Phase I clinical trials in the United States."
News from the battlefront
"In a recent study published in Molecular Cell and conducted in collaboration with researchers in the U.S., we discovered a previously unknown mechanism by which Mdm2 can dangerously decrease the amount of p53 in the cell. We found that Mdm2, in addition to binding directly to p53 and driving its destruction, can reduce p53 levels indirectly – by countering a protein called L26, which plays a pivotal role in p53 synthesis. In other words, Mdm2 can both inhibit the production of the p53 protein and accelerate the demise of the protein that has been produced.
"Before we can tell if this finding could lead to a new drug, scientists must determine whether the binding site between the two molecules, Mdm2 and L26, is structurally a good drug target. If it is, I could envision a drug cocktail that would target two separate mechanisms involving Mdm2 – the one we discovered more than ten years ago and the new, indirect one we discovered recently."
The origins of complexity
"Surely, nature didn't devise several control mechanisms for p53 synthesis just to frustrate cancer researchers. Its goal is to keep p53 levels low when all is well, but to raise them rapidly and efficiently when cancer-causing changes occur in the cell. It's difficult to achieve such a rise with a single mechanism."
The challenges ahead
"Most new-generation drugs for treating cancer are directed at signaling enzymes, which have been extensively studied. These enzymes include receptors that often are easily accessible on the surface of cells, particularly through the use of specific antibodies. In contrast, p53 operates in the cell nucleus, which is more difficult to reach and must be targeted with specially designed small molecules."
Prof. Moshe Oren's research is supported by the Robert Bosch Foundation.
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Prof. Roy Bar Ziv's research is supported by the Phyllis and Joseph Gurwin Fund for Scientific Advancement; and the Carolito Stiftung.